Spinocerebellar ataxia type 1 (SCA1) is one of a series of autosomal dominant cerebellar ataxia. SCA1 patients develop gait ataxia, dysarthda and nystagmuso. As the disease progresses other signs of cerebellar and brainstem dysfunction become apparent with death resulting from loss of bulbar function. Neuropathology in SCA1 includes severe loss of cerebellar Purkinje cells. SCA1 is among a group of neurodegenerative disorders caused by an expansion of a CAG triplet repeat encoding a polyglutamine tract within each respective disease protein. Substantial progress has been made towards understanding the molecular basis of SCA1 pathogenesis. However, several critical questions remain for SCA1 and for polyglutamine disorders in general. These, for the most part, relate to the relative importance of the polyglutamine tract vs. its protein context for driving disease. We propose a model of SCA1 pathogenesis in which disease ensues due to a disruption of nuclear architecture and/or function in specific neurons by mutant ataxin-1 (the SCA1 gene product). In this model, there are predicted to be several points at which residues in Jataxin-1 that, along with the polyglutamine tract, would have a critical role in driving the development and progression of disease. The Aims of this proposal use a genetic approach to test several important aspects of this model in transgenic mice. Understanding the importance of these factors for SCA1 pathogenesis should provide insights for polyglutamine diseases in general.